The long range objective of the proposed research is the definition at the molecular level of the mechanism(s) involved in drug resistance in Plasmodium, the causative agent of human malaria. This proposal is based on the similarity observed between the drug resistance phenotype of tumor cells and Plasmodium spp. One of the genes involved in tumor cells and protozoa resistant to drugs is the gamma-glutamylcysteine synthetase (ggcs) gene. We are working with an in vivo rodent malaria model, which includes sensitive strains of P. berghei as well as several lines with different profiles of drug resistance. The specific aim is: To investigate P. berghei ggcs (pbggcs) gene mRNA upregulation in multidrug resistant lines and drug sensitive ones. The working hypothesis is that upregulation of pbggcs mRNA in resistant parasites is due to mutations at the cis-regulatory regions of the gene. Understanding the mechanisms by which the parasites become resistant will provide the basis for better drug chemotherapy and improved control of this fatal disease.